JP2001511444A - Combination of an HMG-CoA reductase inhibitor and a nicotinic acid compound and method for treating hyperlipidemia once a day at night - Google Patents

Abstract

An extended or sustained release composition for oral administration to alter serum lipid levels in an individual without causing drug-induced hepatotoxicity, rhabdomyolysis or myopathy, the composition comprising from 250 mg to 3000 mg of nicotinic acid or a compound metabolised to nicotinic acid by the body selected from the group consisting of nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminium nicotinate, niceritrol, d,l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-Oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyrridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinicate, hexanicite, ronitol, and methyl, ethyl, propyl or butyl alcohol esters of nicotinic acid or combinations thereof, coated with an immediate release coating of from 0.1 mg to 80 mg of an HMG-CoA reductase inhibitor.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD This invention is administered once daily as a single dose during the night without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis (degeneration). In case,
Nicotinic acid or nicotinic acid compounds in extended release form and mixtures thereof and 3-hydroxy-3-methylgluta in immediate or extended release form useful for altering serum lipid levels in a patient Phosphorus coenzyme A (HMG-C
oA) a pharmaceutical combination for oral administration comprising a reductase inhibitor. The present invention also alters a patient's serum lipid levels, for example, to treat hyperlipidemia and atherosclerosis, without causing drug-induced hepatotoxicity, myopathy or rhabdomyolysis. Thus, it relates to a method of administering such a pharmaceutical combination orally to a patient once a day as a single dose during the night time.

BACKGROUND OF THE INVENTION Hyperlipidemia or elevated serum lipids is associated with cardiovascular disease and increased morbidity of atherosclerosis. Particular forms of hyperlipidemia include, for example, hypercholesterolemia, familial dysbetalipoproteinemia, diabetic dyslipidemia, nephrotic dyslipidemia, and familial combined hyperlipidemia. Hypercholesterolemia is characterized by an increase in serum low density lipoprotein-cholesterol and serum total cholesterol. Low density lipoprotein (LDL-cholesterol) transports cholesterol in the blood. Familial dysbetalipoproteinemia, also known as type III hyperlipidemia, is characterized by the accumulation of very low density lipoprotein-cholesterol (VLDL-cholesterol) particles in serum, called beta-VLDL. Can be
Also associated with this condition is the replacement of normal apolipoprotein E3 with an abnormal isoform of apolipoprotein E2. Diabetic dyslipidemia can be caused by overproduction of VLDL-cholesterol, abnormal VLDL triglyceride lipolysis, reduced LDL-
It is characterized by complex lipoprotein abnormalities, such as cholesterol receptor activity and sometimes type III hyperlipidemia. Nephrotic dyslipidemia is difficult to treat and often includes hypercholesterolemia and hypertriglyceridemia. Familial combined hyperlipidemia is characterized by the combined phenotype of hyperlipidemia, ie, type IIa, IIb, IV, V or hyperapobetalipoproteinemia.

It is well known that if serum lipids, and especially LDL cholesterol, can be reduced, the risk of causing cardiovascular disease can be reduced. It is also well known that if serum lipids can be reduced, the progression of atherosclerosis can be slowed or a reduction in atherosclerosis can be induced. In such cases, individuals diagnosed with hyperlipidemia or hypercholesterolemia may develop atherosclerosis for the purpose of reducing their risk of cardiovascular disease and especially coronary artery disease. Lipid-lowering treatment should be considered to slow down or induce a reduction in atherosclerosis.

[0004] Hypertriglyceridemia is also an independent risk factor for cardiovascular diseases such as coronary artery disease. Many humans with hyperlipidemia or hypercholesterolemia have elevated triglyceride levels. It is known that a decrease in elevated triglycerides can result in a secondary decrease in cholesterol. These individuals should also consider lipid-lowering therapy to reduce elevated triglycerides in these individuals for the purpose of reducing their occurrence of atherosclerosis and coronary artery disease.

[0005] Cholesterol is used as VLDL-cholesterol, LDL-cholesterol and high density lipoprotein-cholesterol (HDL-cholesterol).
Transported in the blood by lipoprotein complexes. LDL carries cholesterol in the blood to the intima space of the vessel wall. Peroxidation of LDL-cholesterol in the intima space of the vessel wall leads to atherosclerotic plaque formation. On the other hand, HD
It is believed that L-cholesterol counteracts plaque formation and delays or prevents the onset of cardiovascular disease and the symptoms of atherosclerosis.
HDL ₁ - cholesterol, HDL ₂ - cholesterol and HDL ₃ - several lower forms of HDL- cholesterol, such as cholesterol have been confirmed so far.

[0006] In the past, to reduce elevated cholesterol levels and HDL
-There have been many methods proposed to increase cholesterol levels. Typically, these methods involve a diet and / or daily administration of a lipid changing agent or a blood lipid lowering agent. Another proposed method is disclosed in U.S. Pat. No. 4,895,55.
No. 8 relates to periodic plasma disruption by a continuous flow filtration system. Several types of hypolipidemic drugs have been developed to treat hyperlipidemia or hypercholesterolemia or normolipidemia diagnosed with cardiovascular disease. In general, these agents work by (1) reducing the production of serum lipoproteins or lipids or (2) by increasing their removal from serum or plasma. Drugs that reduce serum lipoprotein or lipid levels include inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. Examples of HMG-CoA reductase inhibitors include mevastatin, U.S. Patent No. 3,983,140, lovastatin, also referred to as mevinolin,
U.S. Patent No. 4,231,938, Pravastatin, U.S. Patent No. 4,346,2
Nos. 27 and 4,410,629, lactones of pravastatin, US Pat. No. 4,448,979, velostatin, simvastatin, also referred to as synvinolin, US Pat. No. 4,448,784.
No. 4,450,171, rivastatin, fluvastatin, atorvastatin and cerivastatin. Regarding the HMG-CoA reductase inhibitor,
U.S. Pat. Nos. 5,217,992, 5,196,440 and 5,189
No. 5,180, No. 5,166,364, No. 5,157,134, No. 5,
Nos. 110,940, 5,106,992, 5,099,035, 5,081,136, 5,049,696, and 5,049,577
No. 5,025,017, No. 5,011,947, No. 5,010,
No. 105, No. 4,970,221, No. 4,940,800, No. 4,8
Nos. 66,058, 4,686,237, 4,647,576, European Patent Application Nos. 0142146A2 and 0221025A1 and PCT Applications WO86 / 03488 and WO86 / 07054.

[0007] Other pharmaceutical to lower serum cholesterol, nicotinic acid, bile acid sequestrants, such as cholestyramine, colestipol, DEAE-Sephadex (Secholex ^R and Polidexide ^R), the probucol and U.S. Patent No. 3,674,836 Related compounds as disclosed, lipostabil (Rhone-Poulanc), Eisai E5050 (N-substituted ethanolamine derivative), imanixil (
imanixil) (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphoryl-choline (SPC,
Roche), aminocyclodextrin (Tanabe Seiyaku), azinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035
American cyanamide CL-277,082 and CL-283,546 (disubstituted urea derivatives), ronitol (having an alcohol corresponding to nicotinic acid), neomycin, p-aminosalicylic acid, aspirin, quaternary Secondary amine poly (diallyldimethylammonium chloride) and U.S. Pat.
Ionenes as disclosed in US Pat. No. 27,009, US Pat. No. 4,759,9
No. 23, poly (diallylmethylamine) derivatives, omega-3-fatty acids found in various fish oil supplements, fibric acid derivatives (fibr
ic acid derivatives, such as gemfibrodim, clofibrate, bezabibrate, fenofibrate, ciprofibrate and clinofibrate and US Pat. No. 5,200,424. , European Patent Application No. 0065835 A1, European Patent No. 164,698-A, British Patent No. 1,586,152 and British Patent Application No. 2162-179-A.

[0008] Nicotinic acid, also known as niacin, has been used for many years in the treatment of hyperlipidemia or hypercholesterolemia. This compound is useful in the body for total cholesterol, VLDL-cholesterol and VLDL-cholesterol remnants, LDL-cholesterol, triglycerides and "Lp (
a) While reducing apolipoprotein a known as "
-It has long been known to show a beneficial effect of increasing cholesterol.

[0009] Nicotinic acid is usually administered three times a day after a meal. This dosing rule is
lism (34) 7: “Contrasting Effect” on page 642 to page 647 (1985)
s of Unmodified and Time-Release Forms of Niacin on Lipoproteins in Hype
rlipidemic Subjects: Klues to Mechanism of Action of Niacin ”
It is known to provide very beneficial effects on blood lipids as discussed by nopp et al. A major advantage of this profile is the ability of nicotinic acid to increase HDL-cholesterol particles while reducing total cholesterol, LDL-cholesterol, triglycerides and Lp (a). While such provisions produce beneficial effects, skin hyperplasia, etc., often occurs in hyperlipidemic patients to whom nicotinic acid is administered.

To avoid or reduce skin flushing resulting from nicotinic acid therapy, guar gum as reported in US Pat. No. 4,965,252, US Pat.
Mineral salts as disclosed in U.S. Pat. No. 4,911,023,245.
917, and inorganic magnesium salts as reported in PCT Application No. 9
Numerous drugs, such as non-steroidal anti-inflammatory drugs, such as aspirin, as disclosed in US Pat. These agents have been reported to avoid or reduce the skin flushing side effects usually associated with nicotinic acid treatment.

[0011] Other methods of avoiding or reducing the side effects associated with immediate release niacin include:
The use of extended or sustained release formulations. Prolonged or sustained release formulations allow for a slower release of the active ingredient from the tablet or capsule, allowing a reduction in the number of doses compared to typical doses associated with conventional or immediate dosage forms Designed to do. Slow drug release reduces and prolongs the blood level of the drug and thus minimizes or reduces skin flushing side effects associated with conventional or immediate release niacin products. Nicobid ^R Capsule (Rhone-Poulenc Rorer), Endur -acin R (Innovite Corporation) and U.S. Patent No. 5,126 to describe a sustained release niacin formulation containing two different types of hydroxypropyl methylcellulose and a hydrophobic component, 145
No. 5,268,181, extended or sustained release formulations of niacin have been developed.

[0012] Studies have been conducted in hyperlipidemic patients using a number of extended or sustained release niacin products. These studies have shown that an extended or sustained release product does not have the same beneficial lipid altering effects as immediate release niacin and in fact has a worse side effect profile as compared to immediate release products. Metaboli
As reported by Knopp et al. in sm, 34 (7) at pages 642 to 647 (1985), the major disadvantage of sustained release formulations is the rather low reduction in triglycerides (-38% for immediate release). -2% for sustained release against) and a lower increase in HDL-cholesterol (+ 22% for immediate release vs. + 8% for sustained release) and HDL ₂ which is known in the art to be most beneficial -A lower increase in cholesterol (+ 37% for immediate release versus -5% for sustained release).

In addition, extended or sustained niacin formulations are described by Henken et al. (Am. J. Med., 91: 1991 (1991)) and Dalton et al. (Am. J. Med., 93:
102 (1992)), it is known to cause a high incidence of hepatotoxicity. There is also a major problem with regard to the ability of these formulations to break glucose metabolism and uric acid levels.

An earlier edition of the Journal of the American Medical Association (JAMA) provided an article providing research results investigating hepatotoxicity problems associated with sustained release forms of nicotinic acid. JAMA, 271 (9): 672 (March 2,
1994) by McKenney et al., “A Comparison of the Efficacy and T
oxic Effects of Sunstained-vs. Immediate-Release Niacin in Hypercholeste
rolemic Patients. "Of that number, 18% or 78% were retrieved because liver function tests (LFTs) increased the presentation of potential liver damage. The authors of this article Concluded that the sustained release form of niacin "should be restricted for use".

[0015] Similar in representative food and pharmaceutical administration and an article by the title "Hepatic Toxicity of Unmodified and Time-Release Preparations of Niacin" by Rader et al. In Am. J. Med., 92:77 (January, 1999). The conclusion has been reached. These studies and similar conclusions were drawn by other health care professionals.

[0016] HMG CoA reductase inhibitors have also been used for many years to treat hyperlipidemia. These compounds are responsible for total cholesterol and LDL in the human body.
-It is known to show a beneficial effect of lowering cholesterol and raising HDL-cholesterol levels in some individuals (Grundy SM: N.E.
ngl. J. Med. 319 (1): 24-32, 25-26 and 31 (July 7, 1
988)). Conversion of HMG-CoA to mevalonate is an early step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase, which prevents mevalonate production, is the basis for HMG-CoA reductase inhibitors to exert their total and LDL-cholesterol lowering effects (Grundy SM
: N. Engl. J. Med., 319 (1): 24-32, 25 and 26 (July 7, 1988)).

However, HMG-CoA reductase inhibitors are not without their drawbacks.
HMG-CoA reductase inhibitors are described, for example, by Garnett WR in Am. J. Cardio.
1, 78 (Suppl 6A): 20-25 (Sept. 26, 1996); The Lovastati
n Pravastatin Study Group Am. J. Cardiol, 71: 810-815 (A
pril 1, 1993); Amer. J. Med. 91 (Suppl 1B) by Dujovne CA et al.
): 25S-30S (July 31, 1991) and hepatotoxicity, myopathy and striated as reported in Mantell GM et al., Am. J. Cardiol, 66: 11B-15B (Set. 18, 1990). It is known to induce myolysis.

Furthermore, in the Physicians' Desk Reference (PDR) 50th edition (1996), p. 1700, column 3, lovastatin, an HMG-CoA reductase inhibitor, was carefully used in patients with past liver disorders. Must be used,
It has been reported that lovastatin treatment is banned for patients with active liver damage or unexplained sustained elevations in serum aminotransferase. Said one
996 PDR, page 1701, column 1, rhabdomyolysis is associated with lovastatin therapy alone and lipid lowering dose of nicotinic acid (≧ 1 g / day)
Physicians intending to combine lovastatin with a lipid-lowering dose of nicotinic acid should consider the potential benefits and risks carefully. That individuals should be monitored closely for any signs and symptoms of muscle soreness, tenderness, or weakness, and especially during the first few months of treatment and during all periods of elevated dose titration of any medication Further reports. The 1996 PDR further reports in column 1 on page 1701 that cases of myopathy were associated with patients taking lovastatin concurrently with a hypolipidemic dose of nicotinic acid. The 1996 PDR
(1) similar contraindications for fluvastatin in page 2267, column 3 and page 2268, column 1, for pravastatin in page 767, column 1 and for simvastatin in page 1777, column 2. Reporting. Still further, the PDR states in page 768, column 3, that concurrent therapy with the HMG-CoA reductase inhibitor and these agents [lipid-lowering dose of nicotinic acid] is generally not recommended. I have.

Despite the presentation in the 1996 PDR, N. Engl. J. Med, 319 (
1): In 24-33 (July 7, 1988), Grundy SM increases HMG-CoA reductase inhibitor (pages 29 to 30) when used alone and nicotinic acid when used alone. Reported to be effective in reducing cholesterol plasma levels. Grundy, at page 24, column 2, lines 10-25, states, "Because of their potency, bile acid sequestrants (cholestyramine and colestipol) and niacin were probably the first choice for hypercholesterolemia. ----- These medicaments are highly effective and satisfactory for use in many patients with high cholesterol levels, but unfortunately they are not sufficient for all patients. Therefore, despite their proven utility, bile acid sequestrants and niacin are not ideal cholesterol lowering agents. "
Still further, Grundy states on page 30, column 1, lines 13-17, that "administration of [HMG-CoA] reductase inhibitor twice a day for the same total dose of 1
It is somewhat more effective than once daily dosing. Grundy also notes on page 29, column 1, lines 7 to 11, that "the combination of lovastatin with cyclosporine, gemfibrozil or nicotinic acid may cause patients with myopathy and, in some cases, rhabdomyo. It can even make it more susceptible to myolysis. Still further, Grundy states on page 30, column 1, lines 54-59, "The combination of lovastatin and niacin has not been shown to be safe in controlled clinical trials. There were also signs of adverse drug-drug interactions such as myopathy. But by Gardner SF and others.
Pharmacotherapy, 16 (3): 421-423 (1996); Ann Intern Med 125 (7): 529-540 (Oct. 1, 1996) by Pasternak RC et al .; Am. J. Cardiol, 76 by O'Keefe JH et al. : 480-484 (Sept. 1, 1995) and Davignon J et al., Am. J. Cardiol, 73: 339-345 (Feb. 15, 1994).

Vacek JL et al. Am. J. Cardiol, 76: 182-184 (July 15, 1
995), they point out on page 183 that, "owing to the current state of knowledge of the risk of hepatotoxicity using delayed release of nicotinic acid, It should probably not be used in trials and clinical practice [in combination with lovastatin]. "

According to the report by Vacek JL et al. And consistent with the 1996 PDR, Am. J. Cardiol
, 73: 25D-29D (May 26, 1994), by an article by Jacobson TA and Amorosa LF, at pages 28D-29, "Abnormalities in liver enzyme profiles and fulminant hepatic dysfunction are also This has led to the use of niacin, especially sustained release formulations .----- The use of fluvastatin in combination with a sustained release niacin formulation was based on this study, which examined only crystalline, i.e., immediate release niacin. It cannot be generally recommended. "

[0022] Therefore, especially with respect to hepatotoxicity, effects on glucose metabolism, uric acid levels, myopathy and rhabdomyolysis, together with an acceptable safety profile, "balanced lipid changes", ie total cholesterol, LDL- There is a need in the scientific literature to develop a lipid-altering or hypolipidemic drug that provides a patient with a reduction in cholesterol, triglycerides and Lp (a) and an increase in HLD particles and a method of delivering said drug. You can see from

[0023] SUMMARY OF THE INVENTION the invention Summary: In summary, the present invention is the treatment of using the novel HMG-CoA reductase inhibitor / nicotinic acid pharmaceutical combination and such pharmaceutical combination for oral administration The discovery of a method mitigates or overcomes the obvious above-mentioned problems and disadvantages of the current state of HMG-CoA reductase inhibitor treatment and nicotinic acid treatment.

In accordance with the present invention, to alter serum lipid levels in an individual without causing drug-induced hepatotoxicity, rhabdomyolysis or myopathy, eg, reduce hyperlipidemia and atheroma Pharmaceutical combinations for oral administration are provided for inhibiting atherosclerosis. Generally speaking, the pharmaceutical combination of the present invention comprises an extended release form of nicotinic acid, a derivative of nicotinic acid, a compound or any mixture thereof which is metabolized in the body to form nicotinic acid and HMG-CoA reduction Contains enzyme inhibitors. The pharmaceutical combination changes or decreases serum lipid levels such as total cholesterol, VLDL-cholesterol, LDL-cholesterol, Lp (a) and triglyceride levels and increases or increases HDL-cholesterol levels. Administered in an amount that is effective for administration. This may be without causing drug-induced hepatotoxicity, rhabdomyolysis or myopathy, or without adversely affecting glucose metabolism or uric acid levels, or at least as requiring interruption of such treatment. Achieved to a standard without causing such a side effect on a recognizable number of individuals.

According to the present invention, the pharmaceutical combination is administered as a single oral dose once a day. Preferably and for individuals having a typical daytime schedule, the single oral dose may be used to reduce total cholesterol, VLDL-cholesterol, LDL-cholesterol, Lp (a) and triglyceride levels or HDL. At or after dinner to achieve cholesterol levels (some of which lipid components are mainly biosynthesized at night in such individuals) at an effective in vivo level in individuals at night It is administered during the evening hours or at bedtime. The present invention as a single dose at or near their daytime bedtime for individuals having a typical nighttime schedule different from the daytime schedule, e.g., for individuals working during the night and sleeping during the day. It may be preferable to administer a pharmaceutical combination of

When the pharmaceutical combination of the present invention is administered once a day in a single oral dose, the single dose is higher than that obtained with nicotinic acid alone than the total cholesterol, LDL-cholesterol and triglycerides. It has also been found to provide additional reduction. In fact, the pharmaceutical combinations of the present invention when administered as a single oral dose provide a substantially greater extent than any lipid-lowering drug, when administered alone as a single oral dose in equal doses. Reduced total cholesterol, LDL-cholesterol and triglyceride levels. Further, the pharmaceutical combination of the present invention when administered as a single oral dose provides a substantially greater degree of HMG-CoA reductase inhibitor than when administered alone as a single oral dose at equal doses. , Increased HDL-cholesterol levels.
When the pharmaceutical combination of the present invention is administered once a day as a single dose, the single dose may consist of (1) an equal or higher daily dose of nicotinic acid and nicotine administered in divided oral doses HMG-CoA administered separately from split administration of acid
It is also believed that it is at least as effective as a combination of equal daily oral doses of reductase inhibitors and (2) it is less likely to cause hepatotoxicity than divided dose therapy.

Quite surprisingly, the pharmaceutical combinations according to the invention can be used without causing drug-induced liver damage, rhabdomyolysis or myopathy or without adversely affecting glucose metabolism or uric acid levels, for example. Used to effectively treat hyperlipidemia (eg, cholesterol-related cardiovascular disease) and atherosclerosis of complex etiology, and normal lipid status diagnosed or at risk of cardiovascular system Can be done.

The pharmaceutical combination of the present invention comprises (a) an HMG-CoA reductase inhibitor and (b)
A) Preferred medicaments according to the invention, although intended for the combination of an extended release form of nicotinic acid, as well as derivatives of nicotinic acid, compounds metabolized to nicotinic acid in the body and any combination thereof The combination is HM in immediate release form
A pharmaceutical combination for oral administration consisting of a G-CoA reductase inhibitor and nicotinic acid in an extended release form. Preferred HMG-CoA reductase inhibitors include atorvastatin, cervastatin, fluvastatin, lovastatin, pravastatin and simvastatin.

In practicing the method of the present invention, the pharmaceutical combination of the present invention is human and bovine;
It can be administered to other animal species such as dogs, cats, pigs, horses, sheep, rabbits, rats, rats, rodents, monkeys, etc., and as such, tablets, capsules, caplets (Caplet), granules, beads, and the like, can be introduced into conventional systemic dosage forms. Other lipid-altering or blood lipid-lowering agents as well as agents known to reduce but prevent skin flushing, unless such additives do not detract from the purpose of the present invention. It can be included in or administered simultaneously with the pharmaceutical combination under appropriate control to compensate for the beneficial effects.

The present invention also provides a method for reducing or eliminating nicotinic acid-induced flushing, which limits the adaptability of a patient, prior to the start of nicotinic acid treatment, by administering a nonsteroidal anti-inflammatory drug (
(NSAID). Pretreatment with a lower dose of an NSAID, such as aspirin, when used according to a pre-dosing schedule, gradually reduces prostaglandin D ₂ (PGD ₂ ) production and allows for more nicotinic acid administration. Make it possible. In accordance with the present invention, pre-treatment of the patient with the NSAID comprises administering low doses of aspirin at least about 7 days, and preferably at least about 14 days, 1-4 times daily prior to nicotinic acid administration. Like N
Administering a SAID.

The dosage administered should be carefully adjusted according to age, weight, and condition of the patient, and the route, dosage form and administration of the administration, and the desired result.

Thus, for oral administration, from about 250 mg to about 3000 mg, and preferably from about 500 mg to about 2500 mg, and most preferably from about 1000 mg to about 2000 mg.
from about 0.05 mg to about 160 mg, in combination with nicotinic acid at commonly used dosages, as indicated in the 1996 Physician's Desk Reference for nicotinic acid, such as in amounts in the range of mg and Preferably about 0.0
HMG at a dose such as in an amount in the range of 5 mg to 80 mg and more preferably in the range of about 0.2 mg to about 40 mg, for example as indicated in the 1996 Physician's Desk Reference or the packaging insert for these products. Satisfactory results can be obtained using -CoA reductase inhibitor, HMG-CoA
The reductase inhibitor and nicotinic acid are used together, in the same oral dosage form or in separate oral dosage forms, taken simultaneously or almost simultaneously. Therefore, nicotinic acid is, for example, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg
It can be administered daily in increasing amounts of mg, 2000 mg, 2500 mg and 3000 mg. Thus, the oral dosage form of the present invention is, for example, 250 mg, 375 mg
Nicotinic acid can be included in dosages of 500 mg, 750 mg and 1000 mg.

The exact administration for the HMG-CoA reductase inhibitor will depend on the particular H selected.
It depends on the MG-CoA reductase inhibitor. Hence and in accordance with the present invention, oral dosage forms may include lovastatin, atorvastatin (eg, 10 mg, 20 mg, 40 mg or 80 mg) in a dosage of about 10 mg to about 80 mg or more.
atorvastatin), or pravastatin, eg, 5 mg, 10 mg, 20 mg, 40 mg
Or simvastatin in a dose of about 5 mg to about 80 mg or more, such as 80 mg, or fluvastatin in a dose of about 20 mg to 80 mg or more, such as 20 mg, 40 mg or 80 mg; 05 mg, 0. Cerivastatin in dosages of about 0.05 mg to about 0.3 mg or more, such as 1 mg, 0.2 mg and 0.3 mg, may be included to achieve the desired daily dose. I can do it.

Thus and in accordance with the present invention, oral solid dosage forms, such as tablets, comprise about 0.0
It may contain HMG-CoA reductase inhibitor in an amount of 5 mg to about 40 mg and preferably about 0.1 mg to about 20 mg and nicotinic acid in an amount of about 250 mg to about 1000 mg and preferably 500 mg to about 1000 mg. Examples of oral parenteral dosage forms according to the invention include, for example, 250 mg / 5 mg, 500 mg / 5 mg, 750 mg / 5 mg, 25 mg
0 mg / 7.5 mg, 500 mg / 7.5 mg, 750 mg / 7.5 mg, 1000 mg / 7.
5mg, 250mg / 10mg, 500mg / 10mg, 750mg / 10mg, 1000mg /
10mg, 250mg / 20mg, 500mg / 20mg, 750mg / 20mg, 1000mg
/ 20mg, 250mg / 45mg, 500mg / 40mg, 750mg / 40mg and 10mg
At a dosage strength of 00 mg / 40 mg, nicotinic acid / atorvastatin, nicotinic acid /
Fluvastatin, nicotinic acid / fluvastatin, nicotinic acid / lovastatin, nicotinic acid / pravastatin or nicotinic acid / simvastatin tablets and include, for example, 250 mg / 0.05 mg, 500 mg / 0.05 mg, 750 mg / 0.05
mg, 1000 mg / 0.05 mg, 250 mg / 0.1 mg, 500 mg / 0.1 mg, 75
0 mg / 0.1 mg, 1000 mg / 0.1 mg, 250 mg / 0.15 mg, 500 mg / 0
. 15 mg, 750 mg / 0.15 mg, 1000 mg / 0.15 mg, 250 mg / 0.2
mg, 500 mg / 0.2 mg, 750 mg / 0.2 mg, 1000 mg / 0.2 mg, 250
mg / 0.3mg, 500mg / 0.3mg, 750mg / 0.3mg and 1000mg / 0
. Includes nicotinic acid / cervastatin tablets at a dosage strength of 3 mg.

It is therefore an object of the present invention to alter serum lipids for treating patients, for example patients diagnosed with hyperlipidemia, atherosclerosis and lipemia in normal lipid status. (A) HMG-CoA reductase inhibitor and (b)
) To provide a pharmaceutical combination for oral administration comprising nicotinic acid, a derivative of nicotinic acid, a compound metabolized by the body to form nicotinic acid or a combination thereof in sustained release form.

Another object of the present invention is to provide an HMG-CoA reductase inhibitor having an extended release profile for nicotinic acid, a derivative of nicotinic acid, a compound metabolized to nicotinic acid by the body or a mixture thereof and It is to provide an oral solid pharmaceutical combination with extended or immediate release properties.

Still another object of the present invention is to diagnose or produce hyperlipidemia or cardiovascular disease with little or no liver damage, myopathy or rhabdomyolysis. It is to provide a method of using a composition as described above to treat a normal lipid state that may be at risk.

At least one or more of the above objects, together with its advantages over known techniques for the treatment of hyperlipidemia, as will become apparent from the specification hereinbelow, are described below or in patents This is achieved by the invention as claimed.

In general, the present invention relates to an oral type of improved lipid altering or anti-hyperlipidemic medicament using an effective lipid altering or anti-hyperlipidemic amount of an HMG-CoA reductase inhibitor and nicotinic acid The combination provides, for example, about 5% to about 50% by weight of hydroxypropyl methylcellulose with nicotinic acid per 100 parts by weight of the tablet or compound and the tablet is prepared by mixing the tablet or compound with the nicotinic acid. 0
. Coating with from 01% to about 30% by weight of an HMG-CoA reductase inhibitor.

[0040] The present invention also provides about 0.01% to about 30% by weight of an HMG-CoA reductase inhibitor, about 30% to about 90% by weight of nicotinic acid and about 5% by weight. An orally administered lipid altering or anti-hyperlipidemic composition comprising from about 30% by weight of hydroxypropyl methylcellulose.

The present invention also provides a method of treating lipemia in a patient with normal lipid status diagnosed or at risk for hyperlipidemia or cardiovascular disease in a patient with hyperlipidemia. And methods for changing lipid levels in The method comprises providing an effective lipid altering amount of an HMG-CoA reductase inhibitor and nicotinic acid and an immediate or prolonged release of the HMG-CoA reductase inhibitor and an extended release of nicotinic acid. Forming a composition comprising an amount of an excipient. The method also includes the step of orally administering the composition orally to a patient with hyperlipidemia or normal lipid status at night.

According to the present invention, a method of treating hyperlipidemia in a hyperlipidemic patient or lipemia in a patient with normal lipid status comprises the steps of: administering an HMG-CoA reductase inhibitor; Administering an effective lipid-altering amount of a derivative, a compound metabolized by the body to nicotinic acid, or a mixture thereof to a hyperlipidemic patient or a patient in a normal lipid state. The administration is given once daily, preferably in the evening or night, in combination with a pharmaceutically acceptable carrier, to produce a significant reduction in total cholesterol and LDL-cholesterol, as well as triglycerides and Lp ( a) resulting in a considerable decrease in HDL cholesterol.

The above features and advantages of the present invention will be better understood with reference to the following detailed description and examples. The specific methods and formulations that illustrate the invention are illustrative only and should not be regarded as limiting the invention.

[0044] DETAILED DESCRIPTION: In order to provide illustrated and a more complete evaluation and many of the attendant advantages of the present invention, the following detailed description is provided with respect to the novel methods and pharmaceuticals.

The present invention uses an HMG-CoA reductase inhibitor and nicotinic acid, a derivative of nicotinic acid or a compound other than nicotinic acid itself that the body metabolizes to nicotinic acid, or a mixture thereof, and as described herein. Has the same effect as was done.
Nicotinic acid derivatives and other compounds specifically include, but are not limited to, the following compounds: nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritol, d, l -Alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-oxide,
6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methylnicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5 -Carboxamide, Brazilian (
bradilian), sorbinicate, hexanicite
Esters of nicotinic acid, such as, for example, ronitol and lower alcohol esters such as methyl, ethyl, propyl or butyl ester. Each such optional derivative or compound will be collectively referred to herein as a "nicotinic acid compound."

Specific HMG-CoA reductase inhibitors include but are not limited to the following compounds: lovastatin and related compounds as disclosed in US Pat. No. 4,231,938, pravastatin and US Patent No. 4,3
46,227 and 4,448,979, mevastatin and related compounds as disclosed in US Pat. No. 3,983,140, velostatin and simvastatin, and US Pat. Patent No.4,4
Related compounds such as those described in US Pat. Nos. 48,784 and 4,450,171, fluvastatin, atorvastatin, rivastatin, and fluindostatin (Sansan)
doz XU-62-320; fluvastatin, lovastatin, pravastatin, simvastatin and cerivastatin are preferred. Other HMG-CoA reductase inhibitors that can be used in the present invention include, but are not limited to, the following compounds: Mevalonolactone derivatives as disclosed in US Pat. No. 4,613,610 Pyrazole analogs of PCT application WO 86/034
No. 88, indented analogs of mevalonolactone derivatives, 6- [2- (substituted pyrrol-1-yl) alkylpyran-2-as disclosed in US Pat. ON and its derivatives, Searle's SC-4
5355 (3-substituted pentanedioic acid derivative) dichloroacetate, an imidazole analog of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy as disclosed in French Patent No. 2,596,393 2-hydroxy-propanephosphate derivatives, European Patent Application No. 022
2,3-Disubstituted pyrrole, furan and thiophene derivatives as disclosed in 1025A14, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, U.S. Pat. Octahydronaphthalene as disclosed in EP 499,289, European Patent Application No. 01421
Keto analogs of lovastatin as disclosed in US Pat. No. 5,217,838;
No. 992, No. 5,196,440, No. 5,189,180; No. 5,1
Nos. 66,364, 5,157,134, 5,110,134, 5,110,940, 5,106,992, 5,099,035, Nos. 5,081,136, 5,049,696, and 5,049,5
No. 77, No. 5,025,017, No. 5,011,947, No. 5,011
No. 0,105, No. 4,970,221, No. 4,940,800, No. 4
And other known HMG-CoA reductase inhibitors, such as those disclosed in U.S. Pat.

As described above, HMG-CoA reductase inhibitor and nicotinic acid are hyperlipidemias whose symptoms are characterized by the presence of excess fats such as cholesterol and triglycides in the bloodstream. Used in the past for the treatment of According to one aspect of the present invention, an extended or sustained release composition of nicotinic acid coated with an immediate release coating of an HMG-CoA reductase inhibitor is made as an example. "Extended release" or "sustained release" refers to an HMG-CoA reductase inhibitor, nicotinic acid, when administered orally to a patient to be treated. It is understood that it refers to a composition in which the active ingredient, such as a nicotinic acid compound or a mixture thereof, is released over a period of time for absorption into the blood stream. For example, at a dose of about 1500 milligrams of nicotinic acid (hereinafter "mg"), about 100 percent of nicotinic acid is released from about 4 to about 8 hours and preferably within about 6 hours after ingestion. Is preferred.

Although nicotinic acid is released from the pharmaceutical combination in a sustained release manner,
MG-CoA reductase inhibitors can be formulated for immediate release or prolonged release after ingestion. "Immediate release" means that when administered orally to a patient to be treated, the HMG-CoA reductase inhibitor will cause
It is understood to mean complete release from the composition for absorption into the blood stream.

Certain sustained release compositions according to the present invention use an effective lipid altering dose of nicotinic acid, coated with an effective lipid altering dose of an HMG-CoA reductase inhibitor. An “effective lipid-altering dose” or “effective anti-hyperlipidemic amount” refers to the following total cholesterol, LDL- cholesterol, triglycerides and Lp 1 or more of (a), at least some reduction and HDL- at least some increase in cholesterol, and more particularly, for example, HDL ₂ - cholesterol and (or) HDL ₃ - It is understood to mean an amount that has a beneficial effect on the physiology of the patient, including an increase in cholesterol. Its beneficial effects also include some reduction in the ratio of total cholesterol / HDL-cholesterol and in the ratio of LDL-cholesterol / HDL-cholesterol in the patient's bloodstream. In some individuals, the beneficial effects will also include a decrease in apolipoprotein B, a decrease in apolipoprotein E, and / or an increase in apolipoprotein AI. An exemplary effective lipid altering dose of nicotinic acid will be from about 250 mg to about 3000 mg of nicotinic acid administered according to the present invention, as described more fully herein below.
An exemplary effective lipid altering dose of an HMG-CoA reductase inhibitor is about 0.1 mg
~ 80 mg. These amounts will, of course, vary depending on a number of variables, including the physiological need of the patient to be treated.

Preferably, when the sustained release composition is administered orally to a patient, the swelling agent swells in the patient's gastrointestinal tract over time and releases nicotinic acid and / or a nicotinic acid compound over a time period route. A swelling agent that is formulated with nicotinic acid and / or a nicotinic acid compound for release, ie, a sustained release agent, is also included in the sustained release composition according to the present invention. As is known in the art, such swelling agents and their amounts can be pre-selected to limit the time release of the active nicotinic acid component. Such swelling agents include, but are not limited to, polymers such as sodium carboxymethyl cellulose and ethyl cellulose, waxes such as beeswax and natural substances such as gums or gelatin or mixtures of any of the above. Since the amount of swelling agent will vary depending on the type of swelling agent, the need for time release of the patient, etc., it is preferable to use an amount of swelling agent that achieves the purpose of the present invention.

Exemplary and preferred swelling agents are about 5 to 100 parts by weight of tablet or formulation.
Hydroxypropyl methylcellulose in an amount in the range of about 50% by weight. Preferred examples will ensure sustained time release over a period of about 4-8 hours.

[0052] Binders can also be used in the present compositions. Although any known binding material is useful in the present invention, it is preferred to use materials such as one or more of the group of polymers having repeating units of 1-ethenyl-2-pyrrolidone. These polyvinylpyrrolidone polymers are generally about 10,
It has a molecular weight of 000 to 700,000 and is also known as "povidone or PVP".

The amount of binder material will, of course, vary depending on the type of binder and the amounts of other components of the composition. An exemplary amount of povidone in the composition is from about 1 to about 5% by weight of povidone per 100 parts by weight of the total formulation.

Processing aids such as swelling agents, including stearic acid, magnesium stearate, glyceryl behenate, talc and colloidal silicon dioxide, can also be used as known in the art. . An exemplary amount of a swelling agent, such as stearic acid, in the composition is about 0 to 100 parts by weight of tablet or formulation.
. 5 to about 2.0% by weight.

Also in accordance with the present invention, a sustained release composition comprising nicotinic acid and / or a nicotinic acid compound is coated with an HMG-CoA reductase inhibitor for immediate release after oral administration. Is preferred. An exemplary coating according to the present invention comprises an HMG-CoA reductase inhibitor, a plasticizer, a film-forming and / or coating agent and a colorant. Specific examples of plasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, mineral oil and lanolin alcohol, petrolatum and lanolin alcohol,
Including but not limited to polyethylene glycol, propylene glycol, sorbitol, triacetin and triethyl citrate. Exemplary amounts of plasticizers used in the coatings of the present invention are from about 0.01 to about 5% by weight of the tablet.
It is.

Specific examples of film-forming and / or coating agents include sodium carboxymethylcellulose, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectionery sugar, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose. ,
Includes but is not limited to liquid glucose, maltodextrin, methylcellulose, microcrystalline wax, polymethacrylate, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide and zein. Exemplary amounts of film-forming / coating agents in the present coating are from about 0.01 to about 5% by weight of the tablet. Generally speaking, to produce a coating according to the invention, the HM
The G-CoA reductase inhibitor is suspended or dissolved in an aqueous solution of polyethylene glycol and hydroxypropyl methylcellulose and then HM
Up to a thickness containing an effective anti-hyperlipidemic amount of G-CoA reductase inhibitor.
The film-coating process sprays on the extended release tablet. Examples of suitable coating thicknesses according to the present invention are from about 0.1 mm to about 2.0 mm or more.

The active ingredient contains both active substances in the ranges described above, the balance being a physiologically acceptable carrier of the other substance according to accepted pharmaceutical practice, for example about 265 mg in total weight
~ 1650 mg of various sizes of coated extended release tablets can be made. These coated tablets can, of course, be scored to give a divided dose. Gelatin capsules can be similarly formulated.

In accordance with the present invention, such dosage forms are preferably administered once daily in the evening.
It should be administered to an individual under the control of a single dose.

To further finely regulate the dosage regimen, each dosage unit can be administered separately at the same time or at carefully adjusted times. The same result is achieved by the simultaneous presence of the two substances, as blood levels are established and maintained by a regulated regimen of dosing. Each substance can be individually formulated in separate unit dosage forms in a manner similar to that described above.

The combination of the HMG-CoA reductase inhibitor with the nicotinic acid and / or nicotinic acid compound in the same preparation is more convenient and therefore is especially a coated tablet or caplet for oral administration ) Form. However, alternatively, the pharmaceutical combination of the present invention is characterized in that one oral dosage form is formulated for prolonged or sustained release of nicotinic acid or a nicotinic acid compound or a mixture thereof and the other oral dosage form May be comprised of two different oral dosages that can be administered simultaneously, formulated for prolonged or immediate release of the HMG-CoA reductase inhibitor.

Optionally, the oral pharmaceutical combination of the present invention may contain other active ingredients. The present invention also contemplates that other active ingredients can be administered simultaneously with the pharmaceutical combination of the present invention. Examples of other active ingredients are antilipidemic and flushing inhibitors. Specific examples of antilipidemic agents include, but are not limited to, the following agents: bile acid sequestrants, such as cholestyramine, cholestipole, DEAE Sephadex (Secholex ^R and Polidexide). ^R ), probucol and related compounds as disclosed in US Pat. No. 3,674,836, lipostabil (Rhone-Poulenc), Eisai E5050 (N-substituted ethanolamine derivative), imanixil (HOE) -402), tetrahydrolipstatin (THL), iditigmastanyl phosphorylcholine (isit
igmastanyl-phosphorylcholine (SPC, Roche), asinocyclodextrin (Tanabe Seiyaku), azinomoto AJ-814 (azulene derivative), melinamide (meli
namide) (Sumitomo), Sandoz 58-035, American Cyanamide CL-277,
082 and CL-283546 (substituted urea derivatives), neomycin, p-aminosalicyl, aspirin, quaternary amine poly (diallyldimethylammonium chloride) and ionenes as disclosed in US Pat. No. 4,027,009, US Poly (diallylmethylamine) derivatives as disclosed in Patent No. 4,759,923, omega-3-fatty acids found in various fish oil supplements, fibric acid derivatives such as gemfibrozil, Clofibrate, bezafibrate, fenofibrate, ciprofibrate, and clinofibrate and U.S. Patent No. 5,200,424, European Patent Application No. 658834A1, Europe No. 164-698-A No., British Patent No. 1,586,152 No. and British Patent Application No. 2162-179-A
Other known serum cholesterol lowering agents, such as the agents disclosed in US Pat.

Specific examples of flash inhibitors (flushing inhibitors) include, but are not limited to, non-steroidal anti-inflammatory drugs such as aspirin and salicylate; propionic acid such as ibuprofen, flurbiprofen, fenoprofen, Ketoprofen, naproxen, naproxen sodium, carprofen, and suprofen;
Indoleacetic acid derivatives such as indomethacin, etodolac and sulindac; benzeneacetic acids such as acrofenac, diclofenac and fenclofenac; pyrroleacetic acids such as zomepirac and tolectin; pyrazoles such as phenylbutazone and oxyfenbutazone; oxicams such as piroxicam And anthranilic acids such as meclofenamate and mefenamic acid.

In preparing the compositions, the active substance is added in an amount as described above and in accordance with accepted pharmaceutical practice, with a pharmaceutically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer. , Flavor and the like in a particular type of unit dosage form.

Further examples of adjuvants incorporated into tablets are: binders such as tragacanth, gum arabic, corn starch, potato starch, alginic acid and the like; sweeteners, sucrose, aspartase, lactose or saccharin; Flavoring agents such as orange, peppermint, winter green oil, or cherry oil. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a fatty oil. As a coating or to modify the physical dosage form of a dosage unit,
Various other materials may be present. For example, tablets or capsules may be coated with shellac, sugar or both.

Some of the active agents form known pharmaceutically acceptable salts (eg, alkali metal salts, as well as other base and acid addition salts). Thus, reference to a base is intended to include the common salts that are known to be substantially equivalent to the parent compound.

In the practice of the object of the present invention, nicotinic acid, a nicotinic acid compound and / or an HMG-CoA reductase inhibitor (inhibitor, inhibitor) is a tablet (eg,
Manufacture of pharmaceutical compositions for incorporation into various oral dosage forms suitable for oral use, such as rapidly disintegrating tablets, compressed coated tablets, enteric coated tablets), capsules, caplets, sachets for sprinkle administration, etc. It may be formulated into sustained release granules, sustained release particles, sustained release coated particles, or sustained release beads or pellets according to any method known in the art. Additionally, the HMG-CoA inhibitor may be formulated into immediate release granules or coated raw materials for incorporation into the oral dosage forms of the present invention.

A preferred nicotinic acid sustained release dosage form is a Niaspan® tablet. Niaspan® tablets are prepared by compressing nicotinic acid and an HMG-CoA reductase inhibitor into Niaspan® tablets, which are sustained release forms, before preparing the pharmaceutical combination of the present invention. , Nearspan
It can be modified according to the invention to contain HMG-CoA reductase inhibitors during the formation of the pan) ® granules or during the manufacture of the Niaspan® tablet formulation. Alternatively, Niaspan (registered trademark) tablets are coated with a coating containing the HMG-CoA reductase inhibitor in an immediate release form so that the nicotinic acid is in an extended release form and the HMG-CoA reductase inhibitor is in an immediate release form. The pharmaceutical combination of the invention, which is in the form of a formulation, may be formulated.

The present invention also contemplates other combination dosage forms containing an HMG-CoA reductase inhibitor and nicotinic acid, a nicotinic acid compound, or a mixture thereof. For example, such combination dosage forms include bilayer or multilayer tablets containing, for example, immediate or sustained release granules of an HMG-CoA reductase inhibitor and sustained release granules of nicotinic acid, a nicotinic acid compound or a mixture thereof. , Capsules or sachets. Bilayer or multilayer tablets can be prepared by methods known in the art (eg,
Gently emboss the nicotinic acid layer containing the sustained release nicotinic acid granules, add the layer containing the HMG-CoA reductase inhibitor that is deficient or contains the sustained release or swelling material, and add the combined powder. It may be manufactured by compressing to make a bilayer tablet. Optionally, the HMG-CoA reductase layer may further contain other substances such as flash inhibitors (eg, aspirin).

[0069] In a further embodiment, the pharmaceutical combinations of the present invention may be enteric coated to delay disintegration and absorption in the gastrointestinal tract. For example, (1) sustained release nicotinic acid granules or immediate release or sustained release HMG-CoA reductase inhibitor granules are individually enteric coated and compressed to form a tablet or bilayer tablet layer, or (2) ) The tablet itself or its layers are coated with an enteric coating.

Enteric coated dosage forms are not necessarily dissolved or absorbed by humans until they pass through the low pH environment of the stomach and through the relatively high pH of the small intestine. Typical materials conventionally used as enteric coatings include, but are not limited to, cellulose acetate phthalate, polyvinyl acetate phthalate,
There are hydroxypropyl methylcellulose phthalate, and methacrylic acid-methyl methacrylate copolymer. Such substances can be used individually or in combination. To ensure physical strength and processability (eg, to prevent cracking due to stress, low humidity or other factors), additional compounding materials, such as plasticizers (eg, one or more polyethylene glycols or propylene glycols) ) May be added.

To form enteric coated nicotinic acid microspheres or small particles,
Enteric coated nicotinic acid or HMG-CoA reductase inhibitor granules can be prepared by agglomerating niacin powder with one or more enteric coating materials in a fluid bed granulator. Alternatively, all tablets or capsules containing the HMG-CoA reductase inhibitor and / or nicotinic acid can be coated with an enteric coating material.

Typically, the enteric coating process involves administering the dosage form in multiple layers, such as an enteric coating material (eg, EUDRAG available from Rohm).
IT) one or two or more layers of a methacrylate polymer such as S-100), preferably by dipping the heavy tablets or capsules for 5 seconds in a freshly prepared solution of the substance. Coating. Solutions of enteric coating materials are prepared by dissolving an appropriate amount of the material in, for example, 100 ml of a 4: 6 mixture of acetone and isopropyl alcohol. After each dipping, the coating is allowed to air dry (eg, 30 minutes) and then dipped for 5 seconds. A single coating is usually sufficient to prevent the capsule or tablet from dissolving in the stomach. Alternatively, the granules, tablets or capsules are coated or spray dried in standard coating equipment (eg, those typically used in the pharmaceutical industry).

The present invention also inhibits or reduces prostaglandin PGD ₂ synthesis prior to the start of nicotinic acid or nicotinic acid combination therapy, such that the flash response induced by nicotinic acid therapy is reduced or prevented. A method of pre-treating a subject with a non-steroidal anti-inflammatory drug (NSAID) in an amount useful for the subject is contemplated. In the practice of this aspect of the invention, the pre-treatment should begin at least 7 days prior to administration of nicotinic acid, and preferably at least about 14 days. In shorter pre-treatment,
Although it does not provide the subject with sufficient protection against flash, some protection is observed, ie such short pretreatment periods are also implemented within the scope of the present invention.

During pre-treatment of a subject with an NSAID, the selected NSAID is administered orally at least 1 to 4 times a day or more. However, from the viewpoint of the convenience and compliance of the subject, administration is preferably performed three or less times a day, and more preferably once or twice a day. The NSAID may be administered orally as an immediate release dosage form or as an extended release dosage form. Of course, if an extended release dosage form is selected, NSAIDs will require fewer doses per day than comparable immediate release dosage forms,
Provides similar protection against nicotinic acid-induced flash.

While it is preferred to administer the NSAID during pretreatment, the present invention also contemplates continued administration of the NSAID during nicotinic acid or nicotinic acid compound treatment. This can be done by administering the NSAIDS daily as a separate dosage form, or
D is carried out by administering the pharmaceutical ingredient of the present invention containing D. Particularly preferred NSAIDs are indomethacin, ibuprofen, naproxen,
Including aspirin, ketoprofen, flurbiprofen, phenylbutazone, and piroxicam. These NSAIDs are administered at normal doses for the treatment of inflammation. Aspirin is particularly preferred. Aspirin is at least about 60 per day
mg to about 1000 mg, more preferably at least about 80 mg to 650 mg, and most preferably about 80 mg to 325 mg. In the present invention, higher daily doses of aspirin may be consumed to suppress flushing, but at higher doses as well as higher preferred doses there is a risk of causing gastrointestinal upset and ulcers.

While extended release forms are commercially available for some NSAIDs, other extended release formulations can be prepared by one of ordinary skill in the art by conventional methods, or can be prepared by granulation or powder mixing according to the methods described herein. In a step, the NSAID is compounded with nicotinic acid to create an extended release pharmaceutical combination comprising nicotinic acid and the NSAID. Or NSAID
Can be formulated with a HMG-CoA reductase inhibitor in a coating for immediate release of the NSAID. As yet another example contemplated by the present invention,
Extended release nicotinic acid tablets (eg, Niaspan®) are enteric coated for delayed release and then HMG-C for immediate release.
It may be covered with a coating composed of oA reductase and NSAID.

In a further aspect of the present invention, solid pharmaceutical combinations for oral administration may be prepared in various forms. For example, a tablet may be spherical / flat, spherical / convex, elliptical / flat, elliptical / convex or capsule (caplet), and a capsule may be spherical or elliptical. When the tablets are coated according to the present invention, it is believed that the coating is improved if the tablets are oval / convex. For example, by formulating a sustained release nicotinic acid tablet (eg, Niaspan® tablet) into an oval / convex shape, a similar coating on a tablet having, for example, a capsule (caplet) shape can be obtained. In comparison, it is believed that the coating containing the HMG-CoA reductase inhibitor is improved.

The formulation is administered for an extended period of time, ie, as long as elevated serum cholesterol and the likelihood of arteriosclerosis or symptoms persist. To achieve the desired therapeutic effect,
A dosing period of at least 4 weeks is required.

The disclosures of the US patents and patent applications described and cited herein are hereby incorporated by reference in their entirety.

Examples of various embodiments of the present invention are further described with reference to the following examples.

Example I To demonstrate the efficacy of the compositions and methods of the present invention against known anti-hyperlipidemic compositions and methods known in the art, a number of substantially the same compositions are disclosed in accordance with the above disclosure. Prepared. The components and amounts of the composition are shown in Table IB below.

[0082]

[Table 1]

The tablets were prepared by mixing the ingredients. More particularly, the once-daily Niaspan® tablets of the present invention utilize a hydrophilic matrix-controlled drug delivery system. It is a dynamic system consisting of polymer wetting, polymer hydration, and polymer disintegration / dissolution. The mechanisms by which drug release is controlled depend on, for example, initial polymer wetting, gel layer expansion, tablet erosion, and niacin stability. After the initial wetting, the hydrophilic polymer begins to partially hydrate,
Form a gel layer. Water penetrates the tablet to increase the thickness of the gel layer and the drug diffuses out of the gel layer. When the outer layer of the tablet is sufficiently hydrated, it erodes. It is believed that the erosion releases additional drug. The controlled release from this matrix delivery system can be modified depending on the type and molecular weight of the hydrophilic polymer used.

The Niaspan® formulation is available from Niacin, Methoce
l) (registered trademark) E10M Premium, Povidone K90 and Histren
ene) 5016 (stearic acid). Nearspan (registered trademark)
Methocel® E10M Premium is used as the controlled release material of the formulation. Methocel is partially O-methylated,
O- (2-hydroxypropylated) cellulose, available in several grades with different viscosities and degrees of substitution. Methocel is a Dow Chemical (
Dow Chemical).

[0085] Povidone K90 is used as a granulating / binder in Niaspan® formulations. Povidone is a synthetic polymer composed of linear 1-vinyl-2-pyrrolidone groups, and polymers having various molecular weights and those described above are obtained depending on the degree of polymerization. This is characterized by the viscosity in the aqueous solution compared to water and ranges from 10 to 120 when expressed as a K-value. The approximate molecular weight of povidone K90 is 1,
1,000,000. Povidone is a hygroscopic, water-soluble substance. Near span (
Povidone K90 in the Niaspan® formulation is manufactured by ISP (International Specialty Products). Hystene 5016 is utilized as an external lubricant in Niaspan® formulations. Histrene 5016 is a mixture of stearic acid and palmitic acid. The content of stearic acid is about 40.0% or more, and the sum of the two acids is about 90.0% or more. Histren 5016 is manufactured by Witco. See Table IB for details of the Niaspan® formulation.

[0086] Qualitatively, the four tablet strength formulations are identical. The major component of each formulation is a granular mixture of niacin, Methocel® E10M and povidone K90. The granulation step improves compressibility.

[0087]

[Table 2]

The Niaspan® formulation is provided in white caplet type tablets. The size of the caplets depends on the concentration of the product. 375mg and 50
0 mg Niaspan® tablets are compressed with an embossing of approximately 0.687 ″ long × 0.2281 ″ wide. The length and width of 750 mg and 1000 mg are about 0,0.
750 "x 0.320" width. The weight and firmness of the target tablet defines the thickness of the four Niaspan® products. The production of Niaspan® tablets is described generally below.

Niaspan (registered trademark) granulation process flowchart Raw material process flow apparatus Niacin granules High shear granulator Povidone K90 (Little Fort FM130) Methocel E10M (within granules) Purified water ↓ Drying Fluid bed dryer (Kurat fluid bed) (Tourer) ↓ Reduction of wrapping size Crushing (Chemtech Heath Line)

Description of the Niaspan® Granulation Process The Niaspan® granulation raw material is placed in a high shear granulator and granulated. The wet granules are sieved and dried in a fluid bed dryer.
After the drying step is completed, the granules are ground. Milling ensures a uniform particle size during the Niaspan (registered trademark) granulation.

Niaspan (registered trademark) tablet process flow chart Raw material process flow apparatus Niaspan (registered trademark) tablet formulation Methocel E10M -Kelly Histren 5016 Formulation V-Fenturer) (Stearic acid) ↓ Niasharn (TM) tablet production Compress Niasharn (TM) tablet formulation Rotary tablet compression

Description of the Niaspan® Process
®) granules, extragranular Methocel E10M, and Histrene (Hi
(strene) 5016. The amount of each Niaspan® tablet formulation component will depend on the particular Niaspan® dosage form being manufactured (see Table IB). Compress the Niaspan® tablet formulation to form a Niaspan® tablet. The physical properties of Niaspan® tablets are determined by the specific
span) ® Depends on dosage form.

The manufacture of Niaspan® tablets is described in detail below. The initial stages of manufacture are the same for all four tablet concentrations of Niaspan® (375, 500, 750, and 100 mg). Near span (
One batch of Niaspan® granules consists of four each 40.0 kg units of granules that are processed separately but under similar conditions. Four individual granules are sampled, individually tested, and then released for formulation. The base granules are not concentration specific and may be used to produce Niaspan® tablet concentrations.

The ingredients in the base granules are shown in Table IC below:

[0095]

[Table 3]

The raw material is quantitatively placed in a suitably marked double polyethylene lined container using a scale. Purified water (USP) is placed in a suitable container from which it is later pumped during a wet-massing operation.

A Littleford FM130 granulator was charged to a process unit (〜17.4 kg).
) Is filled with approximately half of the required niacin (USP), then about 4.00 kg of Methocel®, USPE10M Premium CR grade: about 1.20 kg of povidone, USP; Niacin SP (~
17.40 kg). Dry and mix the powder bed in a Littleford FM130 granulator fitted with a chopper for about 1 minute. After completion of the 1 minute premix cycle, about 12.0 ± 0.05 kg of purified water (USP) is sprayed onto the powder bed at a rate of about 2.40 ± 0.24 kg / min. Immediately after adding the purified water (USP), granulate the unit for about 5 minutes.

The granulation unit is placed in a double polyethylene lined container and then manually placed in a Glatt bowl through a # 4 mesh screen. Glatt (G
latt) In a bowl, place in a Glatt TFO-60 fluid bed dryer, maintaining the inlet air temperature at about 70 ° C ± 5 ° C. The units are dried using a Computrac (registered trademark) humidity analyzer model MA5A until a humidity level ≦ 1.0% is obtained. The dried granules are placed in an appropriately marked double polyethylene lined drum and mixed.

[0099] The dried and mixed granules are passed through a Kemutec BetaGrind mill fitted with a 1.5 mm sieve operating at about 1500 RPM. The milled granules are placed in a suitably marked double polyethylene backed drum and mixed. The milled granules are sampled, tested by quality control and released for further processing.

The released granule units were analyzed by Patterson-Kelly 20 ft ³ V
Add to the filter, then dispense it for about 10 ± 1 minute, then place in a suitably marked double polyethylene lined container.

As described above, Niaspan® tablets are formulated from regular granules, which are compounded with an appropriate amount of Methocel (USP) E10M Premium CR grade and stearic acid (NF). To achieve the final dosage formulation. Table I
A and IB describe formulations at each of the Niaspan® tablet concentrations of 375 mg, 500 mg, 750 mg and 1000 mg.

Two test groups, each consisting of 11 and 14 people, were created. A blood sample was taken from the patient and total cholesterol, LDL cholesterol, triglycerides, and HDL
Testing for cholesterol establishes baseline levels from which to compare the variability of these lipids. The patient is then treated with the prescription in the table above, and
Administer 00 mg nicotinic acid once daily. After 8 weeks on this regime, patients are again tested for lipid profiles. The results of tests performed at week 8 showing the change in lipid profile as a percent change from baseline are reported in the table below. In this table, positive numbers reflect the percentage increase and negative numbers reflect the percentage decrease.

[0103]

[Table 4]

The data reported in Table II show that LDL levels in Group A patients have a mean reduction of -13.9.
%, Indicating that the decrease in triglycerides was -18.9% and the level of HDL cholesterol, an effective cholesterol, was increased by 23.0% in this group. Similar results were obtained with patients in group B. These studies show that administering a sustained release formulation in the evening or night reduces LDL cholesterol levels equivalent to immediate release niacin on a mg / mg basis, while administering a sustained release formulation in the daytime or on a mg / mg basis. Shows that it shows an excellent reduction of triglycerides. In addition, the increase in HDL cholesterol resulting from the administration of a sustained release formulation in the evening or night was +23 in one group.
. 0% and + 25.3% in another group. So the evening dose is
Once daily administration provides a reduction in LDL cholesterol and a large reduction in triglycerides, resulting in an increase in HDL cholesterol.

Groups A and B also showed that liver enzymes (AST, ALT and alkaline phosphatase), uric acid and fasting glucose levels were at the beginning of the study (to create a baseline) and 2, 4, and Tested at 8 week intervals. The results of these tests are shown in Tables III-VII below.

[0106]

[Table 5]

[0107]

[Table 6]

[0108]

[Table 7]

[0109]

[Table 8]

[0110]

[Table 9]

[0111]

[Table 10]

[0112]

[Table 11]

[0113]

[Table 12]

[0114]

[Table 13]

[0115]

[Table 14]

Additional tests were performed to compare the present invention with the current state of the art and to quantify the degree of improvement that the present invention has over the prior art. This study involved 240 patients administered according to the invention described above. This group was compared to the patient group tested by McKenney et al., Reported above. The results of this test are shown in the table below.
Compare with VIII.

[0117]

[Table 15]

[0118]

[Table 16] "Comparison of efficacy and toxicity of sustained release versus immediate release niacin in hypercholesterolemic patients", McKenney et al., Journal of American.
Medical Association, March 2, 1994; Vol. 271,
No. 9, twice a day, as described on pages 672-677. ^b SR is “released” ^c Administered once a day at night

The results of the comparison of the studies reported in Table VIII show that in the control group (McKenney group), 18, 23, or 78 percent of patients dropped out of the study due to increased liver function test values. It indicates that. The patient withdrew according to the researcher's instructions. In comparison, a group of 240 patients tested in accordance with the present invention had zero shedding based on the same withdrawal criteria. The test results reported above indicate that this sustained release dosage form did not cause an increase in liver function test values (ie, no liver damage)
Uric acid did not increase, and fasting glucose levels were only a 7.5% increase, indicating that indeed with continued treatment.

Thus, the compositions and methods of the present invention suppress hyperlipidemia in hyperlipidemic patients by lowering LDL cholesterol, triglyceride and Lp (a) levels and increasing HDL cholesterol levels. It is clear that it is very effective. The present invention also demonstrates that it does not increase liver function test values, uric acid or glucose levels in hyperlipidemic patients.

Example II To demonstrate the efficacy of the combinations and treatment methods of the present invention on compounds and methods for inhibiting hyperlipidemia, controlled release of nicotinic acid coated with various HMG-CoA reductase inhibitors Anionic compositions were prepared according to the above and below disclosures. The components and amounts of the compositions are listed in Tables IXA and IXB, and the test results are shown in Table X below.
And XI.

[0122]

[Table 17]

[0123]

[Table 18]

The components of the core tablet are compounded as described in Example I to form a sustained release tablet. The sustained release tablet is then coated as follows. Pre-blend lovastatin, Methocel E5 and Pluracol E1450 in a polyethylene bag for about 2-3 minutes. The mixture is then passed through a 710 mm sieve. Place a low shear propeller blade mixer in a stainless steel beaker containing purified water, USP. The mixer speed is adjusted until a vortex is formed. Slowly add the blend mixture in a polyethylene bag into purified water. If necessary, the mixer speed should be adjusted to maintain a vortex during the addition of the dry mixture. Continue mixing until the blend mixture is completely dispersed.

Place the stainless steel beaker on a balance and record the tare weight.
Calculate the net weight of the coating suspension as follows: Net weight of the coating suspension = Coating suspension with tare-Beaker tare weight

Following the production of the coating suspension, the above-mentioned sustained-release tablet is coated as follows. The Hicoater HCT48 / 60 tablet coating machine is first cleaned almost according to the SOP FM700 procedure for cleaning of the Hicoater HCT48 / 60 tablet coating machine. High coater HCT48 /
60 tablet coating machine, 9 liter bread, 0.6 cc gear prop (g
ear prop), single gun spray bar, 2.5mm cap,
And a 1.5 mm nozzle opening.

According to the SOP FM500 procedure for operation of the high coater HCT 48/60 tablet coating machine in manual mode, the spray air pressure should be set to 150 l / min and the pattern air pressure should be set to 100 l / min. . Once the spray and pattern air pressures have been set, the coating suspension is placed on the balance and the suspension supply line is placed in the coating suspension. Then
Place the suspension regression line in another container. The low shear mixer is then placed in the coating suspension and mixing is started. About 60 minutes should be allocated before proceeding to the next step.

After about 60 minutes, switch on the suspension pump line and purge line. When these lines are filled with the suspension, transfer the suspension regression line to the coating suspension container. The solution passing through the gun is about 40 g / according to SOP FM500.
Should be set to minutes.

Next, the nicotinic acid sustained release tablets of the above batch are loaded into a coating machine.
Close the glass door of the machine. Start the inlet and outlet air blowers. Adjust the inlet and outlet air blowers until the flow is 170 (± 20) cfm and the pan vacuum is -1/2 "to 1".

[0130] The tablets are coated as follows. Set the pan on the JOG at 3.5 rpm, turn on for 5 seconds, and turn off for 30 seconds. Switch on the incoming air heater and adjust it to 60 ° C. When the discharge air temperature reaches 40 ° C., the process proceeds to the film coating phase. The pan is set to run for further coating. Pan speed 15rpm
And start spraying. Calculate the coating end point or target coated tablet weight as follows:

Coating end point = Starting tablet weight (mg) × 1.0413 (750 mg) (for 750 mg tablet) Coating end point = Starting tablet weight (mg) × 1.0249 (1000 mg) (for 1000 mg tablet) Coating end point = Starting tablet weight (mg) x 1.0643 (500 mg) (for 500 mg tablets) The coating end point should be approximately ± 10% of the target coated tablet weight range.

The application of the coating suspension is continued until the end point is reached. When the end point is reached, proceed to the next step, cooling. Stop spraying to cool. Set bread to JOG at 3.3 rpm.
Switch off the incoming air heat and allow the coated tablets to cool to about 35 ° C.
Stop pan and switch off inlet and outlet blowers.

For spitting, use the JOG fastener at the front of the machine to turn the pan so that a trap door is on the surface of the product platform. Under the discharge chute, place a tared double polyethylene lined container with the desiccant present in the outer bag. Open the trap door. JOG until coated tablets start discharging
Turn the fasteners. Continue turning the bread and let the product spit out of the bread. Stop the pan and remove the container. The coated sustained release tablets are then weighed.

Example III An examination group consisting of 382 patients was formed. Taking a blood sample from the patient,
And total cholesterol, LDL-cholesterol, triglycerides and HDL
-Testing for cholesterol established a baseline that could be the basis for changes in these lipids. The patients were then restricted in life as follows: As reported in Table X, 258 of the 382 patients received about 2000 mg of Niaspan® once daily at bedtime. Taking, and 122 of 124 patients received about 2000 mg of Niaspan® (two Niaspan® 1000 mg tablets) and 1 HMG- once daily at night before bedtime. CoA reductase inhibitor tablets were taken. More specifically, four patients received two Nierspan® 1000 mg tablets and one fluvastatin 20 mg tablet once daily.
Take at the same time at bedtime; 12 patients receive 1000 mg of Niaspan®
Take 2 tablets and 1 lovastatin 20mg tablet once daily at night before bedtime
69 patients took two Niaspan® 1000 mg tablets and one pravastatin 20 mg tablet at the same time, once a day, at night before bedtime; 27
Patients received two Niaspan® 1000 mg tablets and simvastatin 10
1 mg tablet once daily at the same time before going to bed at night; and 10 patients went to bed with 2 Niaspan® 1000 mg tablets and 1 HMG-CoA reductase inhibitor tablet once a day I took it at the same time the previous night. However, these 10 patients changed HMG-CoA reductase inhibitors differently during the test. Nonetheless, the specific HMG-CoA reductase inhibitors that were taken by these 10 patients were those listed in Table X.

After treatment with an average treatment period of about 43 weeks, the lipid profiles of the patients were examined again. Test results showing the change in lipid profile as a percentage change from baseline are reported in Tables X and XI below. The test results, which show the change in clinical chemistry profile as a percentage change from baseline, are reported in Table XII below, and the upper limit of normal (ULN) for the selected clinical chemistry parameter.
The results showing the number of patients and the percentage of the total patients who scored higher are reported in Tables XIII and XIV below.

[0136] The occurrence or signs of myopathy or rhabdomyolysis were not marked or observed in a population 122 receiving combination treatment according to this Example III.

[0137]

[Table 19]

Table XI also reports the results of the tests performed. See Table XI for more details.
Reported that 53 out of 124 patients who took Niaspan® and an HMG-CoA reductase inhibitor together once daily at night before bedtime as noted above in Example III. Reports complete efficacy data. Table XI also shows complete data for 16 people who took Niaspan® and a bile acid sequestrant (ie, cholestyramine or colestipol) together once daily at night before bedtime. Efficacy data (lipid results) are reported.
Table XI also shows that once daily at night before bedtime, Niaspan® and BAS (bile acid sequestrants, ie, cholestyramine or colestipol) and HMG-
Complete efficacy data (lipid results) are also reported for 15 individuals taking the CoA reductase inhibitor together.

[0139]

[Table 20]

[0140]

[Table 21]

[0141]

[Table 22]

[0142]

[Table 23]

Table XII shows that once a day before going to bed at night, Niaspan® and HMG-CoA
Clinical chemistry parameters (liver function) are reported for all 124 patients taking reductase inhibitors together. Table XII further shows clinical chemistry parameters for 22 patients who took Niaspan® and BAS (a bile acid sequestrant, ie, cholestyramine or colestipol) together once daily at night before bedtime ( Liver function). Table XII also shows that patients taking Niaspan®, BAS (a bile acid sequestrant, ie, cholestyramine or colestipol) and an HMG-CoA reductase inhibitor once daily at night before bedtime. Clinical chemistry parameters (liver function) for 17 individuals are also reported.

[0144]

[Table 24]

[0145]

[Table 25]

In Tables X-XII, positive numbers represent percent increase and negative numbers represent percent decrease.

Table XIII reports the number and percentage of patients in the total test patients who recorded higher than the upper normal limit (ULN) for the selected clinical chemistry parameter. More specifically, Table XIII shows the ULN for selected clinical chemistry parameters of 124 patients taking Niaspan® and an HMG-CoA reductase inhibitor once daily at night before bedtime. Number and percentage of patients who recorded higher values
Has been reported. Table XIII further shows that selected 22 of 22 patients who took Niaspan® and BAS (a bile acid sequestrant, ie, cholestyramine or colestipol) together once daily at bedtime night. We report the number and percentage of patients who scored higher than ULN for clinical chemistry parameters. Table XIII also shows that once daily at night before bedtime, Niaspan® and BAS (bile acid sequestrants, ie cholestyramine or colestipol) and HMG-
We report the number and percentage of 17 patients who took CoA reductase inhibitors that scored higher than ULN for selected clinical chemistry parameters out of 17 patients co-administered.

[0148]

[Table 26]

Table XIV shows the upper normal limit (ULN) for the clinical chemistry parameters AST and ALT.
The number of patients and the percentage of the total number of patients who recorded values twice or three times higher are reported. More specifically, Table XIV shows ULN for clinical chemistry parameters AST and ALT in 124 patients taking Niaspan® and an HMG-CoA reductase inhibitor once daily at night before bedtime. We report the number and percentage of patients who scored twice or three times higher. Table XIV is consistent with that reported in Table XIII.

[0150]

[Table 27]

The data reported in Tables XI-XIV demonstrate the following: Drug combinations of the invention taken together once daily at night before bedtime, for example, sustained release nicotinic acid And an immediate release HMG-CoA reductase inhibitor in combination with serum lipid levels, especially total cholesterol, VLDL-cholesterol, LDL-cholesterol,
Effective in lowering levels of triglycerides, apolipoprotein B and Lp (a), and in lowering total cholesterol-to-HDL-cholesterol ratio and LDL-cholesterol-to-HDL-cholesterol ratio . Tables XI-XIV also demonstrate the following: Drug combinations of the invention taken together once daily at night before bedtime, for example, sustained release nicotinic acid and immediate release HMG-CoA reductase The inhibitor combination is effective to enhance or increase HDL-cholesterol levels. It is also believed that the data reported in Tables XI-XIV demonstrate the following: Drug combinations of the invention taken together once daily at night before bedtime, eg, sustained release nicotine Acid and immediate release HMG-
The combination of CoA reductase inhibitors may be sustained release nicotinic acid or immediate release HMG-
Either of the CoA reductase inhibitors is more effective at lowering LDL-cholesterol levels than when given in similar amounts but once daily at night before bedtime. Still further, the data reported in Tables XI-XIV are believed to demonstrate the following: Drug combinations of the invention taken together once daily at night before bedtime, for example, sustained release The combination of nicotinic acid and the immediate-release HMG-CoA reductase inhibitor is more effective when the immediate-release HMG-CoA reductase inhibitor is given alone at the same dose once a day at night before bedtime. Are also more effective in increasing HDL-cholesterol levels.

The data reported in Tables XI-XIV also demonstrate that such concurrent treatments include, for example, sustained release nicotinic acid given once daily and at night before bedtime and immediate release HMG-CoA reductase inhibitors can be used to induce hepatotoxicity, without causing hepatotoxicity, myopathy or striated muscle degeneration, or at least to a level that requires discontinuation of such treatment in a substantial population. It can be administered without inducing muscle damage or striated muscle degeneration, and benefits are achieved. In addition, Tables XI-
The data reported in XIV demonstrates that such concurrent treatments, such as sustained release nicotinic acid and immediate release HMG given once daily in the night before bedtime
The CoA reductase inhibitor does not adversely affect glucose metabolism or uric acid levels, or at least does not adversely affect glucose metabolism or uric acid levels to the extent that such treatment is required in a substantial population; Can be administered and the benefits are achieved.

[0153] Based on the above disclosure, it should now be apparent that the drug combinations, formulations, compositions and methods described herein and their use will accomplish the above objects. Thus, obvious variations in drug combinations, formulations, compositions, and methods are within the scope of the invention, and the choice of particular component components is therefore determined without departing from the scope of the invention disclosed and described herein. be able to. According to the invention, for example, sustained release additives, binders and processing aids are not necessarily limited to those exemplified above. Accordingly, the present invention extends to all modifications and variations that fall within the scope of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/06 A61P 3/06 9/10 9/10 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, G , GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Dan, Josephine United States of America Florida, Miami, Two Oakwood Boulevard Suite 140 F-term (reference) 4C076 AA31 AA37 AA40 AA45 AA51 AA54 BB05 CC21 DD41 EE16 EE23 EE32H 4C084 AA19 AA23 NA06 NA07 NA12 ZB112Z 4C086 BA17 BB02 BC05 BC13 BC17 BC19 BC36 BC70 DA17 DA34 EA16 EA20 FA03 FA07 MA02 MA03 MA04 MA09 MA10 NA06 NA07 NA12 ZC33

Claims (54)

[Claims] 1. A once-daily pharmaceutical composition for altering lipids of an individual without causing drug-induced hepatotoxicity, myopathy or striated muscle degeneration, wherein the composition alters lipids. A pharmaceutical composition comprising a controlled release amount of a nicotinic acid compound or a combination of a nicotinic acid compound in a sustained release form and an HMG-CoA reductase inhibitor in an amount effective to alter lipids. 2. The pharmaceutical composition of claim 1, wherein said HMG-CoA reductase inhibitor is in a sustained release or immediate release form. 3. The method according to claim 1, wherein the HMG-CoA reductase inhibitor is atorvastatin.
(atorvastatin), cerivastatin (cerivastatin), flavastatin (flavastatin)
), Lovastatin, pravastatin and simvastatin. The pharmaceutical composition of claim 2, wherein the composition is selected from the group consisting of: 4. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition is in the form of a solid oral dosage form. 5. The solid oral dosage form is a tablet, capsule, caplet
The pharmaceutical composition according to claim 4, which is selected from the group consisting of (caplet), granules, particle beads or pellets. 6. The pharmaceutical composition of claim 5, wherein said solid oral dosage form is enteric coated. 7. The solid oral dosage form is a bilayer tablet having a first layer and a second layer, wherein the first layer contains a nicotinic acid compound or a combination of nicotinic acid compounds,
The pharmaceutical composition according to claim 4, wherein the second layer contains an HMG-CoA reductase inhibitor. 8. The pharmaceutical composition of claim 7, wherein said first or second layer contains an effective amount of nicotinic acid to alter lipids. 9. The pharmaceutical composition of claim 7, wherein said solid dosage form further comprises a third layer, said third layer containing an amount of nicotinic acid effective to alter lipids. . 10. The pharmaceutical composition of claim 7, wherein said bilayer tablet is an enteric-coated bilayer tablet. 11. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition further comprises a coating. 12. The pharmaceutical composition according to claim 11, wherein said coating contains said HMG-CoA reductase inhibitor. 13. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition further comprises nicotinic acid in an amount effective to alter lipids. 14. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition further comprises a flushing inhibitor for reducing the ability of the nicotinic acid compound or combination of nicotinic acid compounds to induce a flushing reaction in an individual. 15. The pharmaceutical composition of claim 14, wherein said flushing inhibitor is a non-steroidal anti-inflammatory agent. 16. The non-steroidal anti-inflammatory agent may be indomethacin, sulindac, etodolac, aspirin, salicylate, ibuprofen, fluribprofen, fenoprofen, suprofen, benoxaprofen, ketoprofen, carprofen. , Naproxen, naproxen sodium, aclofenac, diclofenac, fenclofenac, tolmectin (tolmectin), zomepirac, meclofenamate, mefanamic acid, oxyfenbutazone, phenylbutazone and piroxicam 16. The pharmaceutical composition of claim 15, wherein the composition is selected from the group consisting of: 17. The pharmaceutical composition may further comprise nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl. Nicotinate, 6-OH-nicotinic acid, nicotinaria acid
acid), nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5 -Selected from the group consisting of lower alcohol esters of carboxide, N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinicate, hexanicite, ronitol, and nicotinic acid. 3. The pharmaceutical composition of claim 2, comprising a nicotinic acid compound. 18. The pharmaceutical composition may further comprise nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotine acid,
Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-
Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N
-Methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide,
14. The pharmaceutical composition of claim 13, comprising a nicotinic acid compound selected from the group consisting of N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid, hexanite, lonitol, and lower alcohol esters of nicotinic acid. . 19. The pharmaceutical composition further comprises nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotine acid,
Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-
Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N
-Methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide,
15. The pharmaceutical composition of claim 14, comprising a nicotinic acid compound selected from the group consisting of N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid, hexanite, lonitol, and lower alcohol esters of nicotinic acid. . 20. The pharmaceutical composition of claim 1, further comprising a bile acid sequestrant, an N-substituted ethanolamine derivative, an azulene derivative, a disubstituted urea derivative, an ionene, The pharmaceutical composition of claim 2, comprising a lipid altering agent selected from the group consisting of poly (diallylmethylamine) derivatives, ω-3-fatty acids and fibric acid. 21. The pharmaceutical composition of claim 21, further comprising an effective amount to alter lipids, cholestyramine, colestipol, DEAE Sephadex, probucol, lipostabil, Eisai E5050 (an N-substituted ethanolamine derivative), Imanixil (HOE-402) tetrahydrolipstatin (THL), isitigmastanyl phosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene derivative), melinamide, neomycin, quaternary Lipid alteration selected from the group consisting of secondary amine poly (diallyldimethylammonium chloride), gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate 3. The pharmaceutical composition of claim 2, comprising an agent. 22. A coated tablet for oral administration for altering lipids of an individual without causing drug-induced hepatotoxicity, myopathy or striated muscle degeneration, which is effective for altering lipids. An amount of nicotinic acid compound or combination of nicotinic acid compounds in sustained release form and an amount of HMG- effective to alter lipids.
Such coated tablets comprising a CoA reductase inhibitor in immediate release form. 23. The coated tablet of claim 22, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, flavastatin, lovastatin, pravastatin and simvastatin. 24. The coated tablet of claim 22, wherein said coated tablet is oval and flat or oval and convex. 25. The coated tablet of claim 22, wherein said coated tablet is circular and flat or circular and convex in shape. 26. The coated tablet of claim 22, wherein said coated tablet is in the form of a capsule. 27. The coated tablet has an enteric coating.
A coated tablet according to claim 22. 28. The coated tablet of claim 22, wherein said coated tablet further comprises nicotinic acid in an amount effective to alter lipids. 29. The coated tablet of claim 22, wherein said coated tablet further comprises a flushing inhibitor for reducing the ability of the nicotinic acid compound or combination of nicotinic acid compounds to induce a flushing response in an individual. 30. The coated tablet of claim 29, wherein said flushing inhibitor is a non-steroidal anti-inflammatory agent. 31. The non-steroidal anti-inflammatory agent, wherein indomethacin, sulindac, etodolac, aspirin, salicylate, ibuprofen, fluibuprofen, fenoprofen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, naproxen sodium, naproxen sodium, 31. The coated tablet of claim 30, wherein the coated tablet is selected from the group consisting of aclofenac, diclofenac, fenclofenac, tormectin, zomepirac, meclofenamate, mefanamic acid, oxyfenbutazone, phenylbutazone and piroxicam. 32. The coated tablet of claim 29, wherein said coated tablet further comprises an amount of nicotinic acid effective to alter lipids. 33. The nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotinic acid ,
Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-
Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N
-Methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide,
23. The coated tablet of claim 22, wherein the tablet is selected from the group consisting of N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid, hexanite, lonitol, and lower alcohol esters of nicotinic acid. 34. The coated tablet further comprises nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotinic acid , Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH
-Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide,
From N-methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid, hexanite, lonitol, and lower alcohol esters of nicotinic acid 29. The coated tablet of claim 28, comprising a nicotinic acid compound selected from the group consisting of: 35. The coated tablet further comprises nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotinic acid , Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH
-Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide,
From N-methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid, hexanite, lonitol, and lower alcohol esters of nicotinic acid 30. The coated tablet of claim 29, comprising a nicotinic acid compound selected from the group consisting of: 36. The coated tablet further comprises a bile acid sequestrant, an N-substituted ethanolamine derivative, an azulene derivative, a disubstituted urea derivative, ionene, poly (diallylmethyl) in an amount effective to alter lipids. Amine) derivatives,
including a lipid altering agent selected from the group consisting of ω-3-fatty acids and fibric acid,
A coated tablet according to claim 22. 37. The coated tablet further comprises an amount of cholestyramine, colestipol, DEAE Sephadex, probucol, lipostavir, Eisai E5050 (an N-substituted ethanolamine derivative) effective to alter lipids.
Imanixil (HOE-402) tetrahydrolipstatin (THL), ishitigumatanil phosphorylcholine, aminocyclodextrin, Ajinomoto AJ-81
4 (azulene derivative), melinamide, neomycin, quaternary amine poly (diallyldimethylammonium chloride), gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate, and a lipid altering agent selected from the group consisting of clinofibrate. 23. The coated tablet of claim 22, 38. A method for altering lipids in an individual without causing drug-induced hepatotoxicity, myopathy or striated muscle degeneration, comprising administering an amount of a sustained-release form effective to alter lipids. Administering to the individual once daily a single dose of a nicotinic acid compound or a combination of a nicotinic acid compound and a drug combination comprising an HMG-CoA reductase inhibitor in an amount effective to alter lipids. Method. 39. The method of claim 36, wherein said administering step comprises administering the drug combination as a single dose once a day during the evening. 40. The method of claim 36, wherein said administering step comprises administering the drug combination as a single dose once daily at bedtime or at bedtime. 41. The method is selected from the group consisting of VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, Lp (a), total cholesterol, triglycerides, apolipoprotein AI, apolipoprotein B and apolipoprotein E. 40. Alter one or more of the lipids.
the method of. 42. The method of claim 39, wherein said method increases HDL-cholesterol levels in an individual's serum. 43. The method of claim 39, wherein said method increases apolipoprotein AI levels in an individual's serum. 44. The method according to claim 26, wherein the method comprises the steps of total cholesterol in the serum of the individual versus HDL.
40. The method of claim 39, wherein the method reduces cholesterol levels. 45. The method according to claim 15, wherein the method comprises the steps of:
40. The method of claim 39, wherein the HDL-cholesterol ratio is reduced. 46. The method of claim 39, wherein the HMG-CoA reductase inhibitor is in an immediate release or sustained release form. 47. The method of claim 39, wherein the method comprises the further step of administering to the individual a flushing inhibitor to reduce the ability of the nicotinic acid compound or combination of nicotinic acid compounds to induce a flushing response in the individual. the method of. 48. The flushing inhibitor is a non-steroidal anti-inflammatory agent.
the method of. 49. The non-steroidal anti-inflammatory agent may be an indomethacin, sulindac, etodolac, aspirin, salicylate, ibuprofen, fluibuprofen, fenoprofen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, naproxen sodium, acrofenac ,
49. The method of claim 48, wherein the method is selected from the group consisting of diclofenac, fenclofenac, tormectin, zomepirac, meclofenamate, mefanamic acid, oxyfenbutazone, phenylbutazone, and piroxicam. 50. The nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotinic acid, Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5 -Carboxide, N-
Methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid,
40. The method of claim 39, wherein the method is selected from the group consisting of hexanisite, lonitol, and lower alcohol esters of nicotinic acid. 51. The nicotinic acid compound is nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, l-α-tocopheryl nicotinate, 6-OH-nicotinic acid, Nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5 -Carboxide, N-
Methyl-4-pyridone-5-carboxamide, Brazilian, sorbinic acid,
48. The method of claim 47, wherein the method is selected from the group consisting of hexanisite, lonitol, and lower alcohol esters of nicotinic acid. 52. The method as described above, wherein the method comprises the steps of: providing a bile acid sequestrant, an N-substituted ethanolamine derivative, an azulene derivative, a disubstituted urea derivative, ionene, poly (diallylmethylamine) in an amount effective to alter lipids 40. The method of claim 39, further comprising the step of administering to the individual a lipid altering agent selected from the group consisting of a derivative, an omega-3-fatty acid and fibric acid. 53. The method according to claim 53, wherein the method comprises the steps of: cholestyramine, colestipol, DEAE Sephadex, probucol, lipostavir, Eisai E5050 (an N-substituted ethanolamine derivative), imanixil (
HOE-402) tetrahydrolipstatin (THL), ishitigumastanil phosphorylcholine, aminocyclodextrin, Ajinomoto AJ-814 (azulene derivative), melinamide, neomycin, quaternary amine poly (diallyldimethylammonium chloride), gemfibrozil, Fibrate, bezafibrate,
40. The method of claim 39, further comprising the step of administering to the individual a lipid altering agent selected from the group consisting of fenofibrate, ciprofibrate and clinofibrate. 54. The method of claim 50, wherein said method comprises the further step of administering to the individual an amount of nicotinic acid effective to alter lipids.